Schizophrenia, Schizophrenia-related psychoses - Comment Key Questions - AHRQ Effective Health Care Program

Background
Schizophrenia, Schizophrenia-related psychoses
Schizophrenia is a heterogeneous syndrome that includes disturbances in language, perception, cognition, social relatedness, and volition.1 Symptoms include positive (i.e., delusions, hallucinatory behavior) and negative (i.e., passive/apathetic social withdrawal, blunted affect) symptoms, and general psychopathology (i.e., preoccupation, lack of insight, motor retardation). Onset of symptoms typically occurs in late adolescence/young adulthood, with approximately 0.4 to 0.6% of the population affected.2 Antipsychotics represent the first line treatment for patients with schizophrenia and have been the mainstay treatment since the 1950s. The American Psychiatric Association currently recommends that selection of antipsychotic should be based on discussions regarding previous responses and side-effect profiles.3

Conventional antipsychotics, termed typical antipsychotics (i.e., haldol, chlorpromazine), act on the dopaminergic system blocking the dopamine type 2 (D2) receptors.4 This mechanism, however, leads to a variety of side effects (e.g., extrapyramidal side effects [EPS]) and with long-term exposure (e.g., tardive dyskinesia [TD]).5-6 While these antipsychotics are effective against the ‘positive’ symptoms of schizophrenia (i.e., delusions and hallucinatory behavior), they have been considered relatively ineffective in treating negative symptoms.7 Such symptoms, in particular, play a critical role in producing the severe social and vocational disabilities experienced by many patients with schizophrenia.8

The search for antipsychotic medications to manage both the positive and negative symptoms of schizophrenia led to the re-establishment of clozapine in the early 1990s, and signaled a new generation of antipsychotic drugs (termed ‘atypical’ antipsychotics). A series of atypical compounds have been developed (i.e., risperidone, olanzapine, quetiapine). Compared to typicals, greater benefits of the atypical antipsychotic drugs in many outcome domains have been observed9 and newer medications are replacing the conventional antipsychotics as treatments of choice. Although atypical antipsychotics were developed to improve on the shortcomings of typical antipsychotics, they also have significant limitations in terms of side effects. As a class, they have a more favorable side-effect profile in terms of EPS and TD, but produce side effects, including sedation, hypotension, weight gain, and sexual dysfunction.10 They have been associated with metabolic system side-effects.10 It is unclear whether these metabolic effects are secondary to weight gain, independent, or causative. The long-term consequences are also largely unknown.11

There is debate surrounding the efficacy of atypical antipsychotics on negative symptoms with several papers indicating there is no clear advantage over typical antipsychotics.8,12 Atypical antipsychotic trials have been critiqued for their: (1) inclusion of patients with positive and negative symptoms, making it unclear whether a drug is having direct effects on primary negative symptoms, indirect effects, or both;12 and (2) derivation of data on negative symptoms using short-term trials that focus on patients selected on the basis of positive symptoms (or, for longer-term trials, on the basis of clinical stability).8 Recent findings from the CutLASS 1 (Commentary on Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study)13-14 and CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness)15-16 studies found few differences in effectiveness between atypical and typical antipsychotics in patients with non-refractory schizophrenia. Subsequent meta-analyses have generally confirmed these results17 and help to provide a clearer picture of the comparative effectiveness of the two classes of antipsychotics.

The disconnect between research findings of the CutLASS 1 and CATIE studies and meta-analyses (favoring neither atypicals nor typicals), individual efficacy trials (pharmaceutical industry trials favoring atypicals), and prescribing patterns of clinicians (favoring atypicals), however, make a review of this literature an important step to bringing together research of rigorous and complementary design for clinical decision making and policymaking.

Our preliminary literature scan of MEDLINE and EMBASE (1987 to present; English language) identified 16 reviews and our scan of the Cochrane Library (1999 to present) identified 12 reviews. Combined, these reviews included ~158 different RCTs that focused on a variety of outcomes in relation to use of typical vs. atypical antipsychotics. Comparisons and outcomes included:

1. all first generation typicals vs. clozapine, olanzapine, risperidone, or quetiapine18

2.Outcomes examined: metabolic adverse events (AEs)
pooled ‘conventionals’ (haloperidol, perphenazine) vs. risperidone, olanzapine, or clozapine19-20
Outcomes examined: symptom response, study withdrawal rate, AEs, quality of life (QOL), well-being, sleep, treatment satisfaction, relapse/re-hospitalization rate

3.haloperidol vs. iloperidone,21 aripiprazole,22-26 olanzapine,20,27-34 risperidone,19,30-31,33,35-36 clozapine,30-31,36-39 molindone,40 or quetiapine41-42
Outcomes examined: symptom response, AEs, dosing/tolerability, time to hospitalization, treatment satisfaction/dissatisfaction, QOL, early study withdrawal/dropout rate, relapse/re-hospitalization rate, readiness for hospital discharge, well-being, duration of hospital stay, emergency department visits, social functioning, ability to work

4.chlorpromazine vs. clozapine,30,37-39 olanzapine,20,30 molindone,40 aripiprazole,25 or quetiapine42
Outcomes examined: symptom response, AEs, treatment satisfaction, ability to work, readiness for hospital discharge, relapse rate, ability to work, hospitalization rate, well-being, QOL, time to medication discontinuation, concomitant drug treatment

5.thioridazine vs. clozapine37-38
Outcomes examined: symptom response, AEs, treatment satisfaction, ability to work, readiness for hospital discharge, relapse rate, ability to work, hospitalization rate

6.perphenazine vs. risperidone,35,43 aripiprazole,25 or clozapine43
Outcomes examined: symptom response, AEs, early study withdrawal/dropout rate

7.molindone vs trifluoperazine or thioridizine40
Outcomes examined: symptom response, AEs, early study withdrawal/dropout rate

8.loxapine vs. risperidone or clozapine44
Outcomes examined: symptom response, AEs, early study withdrawal/dropout rate

9.flupenazine vs. olanzapine20
Outcomes examined: symptom response, AEs, relapse/re-hospitalization rate , well-being, early study withdrawal/dropout rate

10.One other review focused on gene polymorphisms and the metabolic syndrome in patients taking atypical or typical antipsychotics.45

Meta-analysis or meta-regression was conducted in 27 of the 28 reviews. As a collective, the reviews have included literature published from 1966 up to 2008. The majority of reviews examined specific AEs and efficacy in reducing positive and negative symptoms. Patients with early-onset and treatment-resistant schizophrenia are represented in several of the reviews.

Also identified were a number of potential RCTs/CCTs for this topic (n?606) that far exceeded the number of trials included in the aforementioned reviews. One RCT, currently active (not recruiting) was also identified in clinicaltrials.gov. Our literature scan also identified ~1,107 comparative observational studies for potential inclusion in our review, which will help to identify emerging evidence on a broader range of outcomes (long-term safety and effectiveness) as well as functional outcomes related to symptom management and quality of life.

Bipolar Disorder
Bipolar disorder is characterized by severe fluctuations in mood, activity, thought and behavior.1 The disorder involves one or more episodes of mania or mixed mood, mood states that are associated with increased psychomotor activity, excessive social extroversion, decreased need for sleep, impulsivity, impairment in judgment and grandiose mood. Patients may experience delusions and paranoid thinking in extremely agitated states. Bipolar II disorder is characterized by at least one hypomanic episode and at least one major depressive episode; with this disorder, depressive episodes are more frequent and more intense than manic episodes. Prevalence of bipolar disorder is 0.4 to 1.6% in community samples and has an average age of onset of 20.1 The American Psychiatric Association (2002) recommends the following for treatment: (1) polytherapy: use of lithium or valproate in conjunction with an antipsychotic for severe manic or mixed episode depression; and (2) monotherapy: use of lithium, valproate or an antipsychotic for less ill patients. The APA states that atypical antipsychotics are preferred over typical antipsychotics because of their side effect profile.46

Our preliminary literature scan of MEDLINE and EMBASE (1987 to present; English language) identified 2 reviews and our scan of the Cochrane Library (1999 to present) identified 3 reviews. Combined, these reviews included ~14 different trials or observational studies. One review provided an overview of the state of evidence for older adults (?60 years) often with reference to one or two drugs as a proxy for the drug class (atypical or typical).47 Outcomes examined in this review were symptom response, AEs, and dosing. Two reviews presented pooled comparisons of haloperidol vs. olanzapine28,48 or risperidone.49 Outcomes examined in these reviews included: symptom response (including time to onset of response), rates of rescue medication usage, AEs, and study withdrawal/dropout rate. One review examined AEs, study withdrawal/dropout rate due to symptom relapse and hospital admissions in olanzapine vs. placebo.50

Also identified were a number of potential RCTs/CCTs for this topic (n?107 trials). Twenty-four trials, currently recruiting, and 5 trials (active, not recruiting) were also identified in clinicaltrials.gov. Our literature scan also identified ~131 observational studies for potential inclusion in our review, which will help to identify emerging evidence on a broader range of outcomes (long-term safety and effectiveness) as well as functional outcomes related to symptom management and quality of life.

Summary
Based on our preliminary literature scan:
(1) A comparative effectiveness review of primary studies would be useful for examining long-term treatment adherence, persistence, functional outcomes, patient satisfaction, health system utilization, and health-related QOL in both schizophrenia/schizophrenia-related psychoses and bipolar disorder. This focus would be a unique contribution to the body of evidence. Systematic reviews indicate these outcomes of interest have been examined for both typical and atypical medication use with schizophrenia, for example, but have not yet been comprehensively synthesized.
(2) Already published systematic reviews of bipolar disorder should be examined for quality and scope using an overview of reviews approach51 to help determine if a review of primary studies is warranted for safety/efficacy data or if an overview of reviews will effectively answer the research question.
(3) An overview of reviews51 would be an efficient approach to synthesizing an already well-published body of literature for short-term efficacy and safety in schizophrenia/schizophrenia-related psychoses.



Analytic Framework
Provisional analytic framework for evaluating the comparative effectiveness of atypical and typical antipsychotics for use in adults with schizophrenia or other psychotic illnesses (Sz) or bipolar disorder (BPD).

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Population(s)
Adults (aged 18 to 64 years) with a DSM-III-R or DSM-IV diagnosis of:

(1) Schizophrenia, Schizophrenia-related psychoses
Including schizophreniform-, delusional- and schizoaffective disorders; first episode schizophrenia, patients refractory to treatment, prodromal schizophrenia

(2) Bipolar Disorder
Including manic or depressive phases (also including Bipolar II disorder), rapid cycling, mixed states

Interventions
Antipsychotic medications currently available on the market in the United States:

Atypical Antipsychotics (brand names in brackets): aripiprazole (Abilify), asenapine (Saphris), clozapine (Clozapine, Clozaril), iloperidone (Fanapt), olanzapine (Olanzapine, Zyprexa, Zyprexa Zydis), paliperidone (Invega, Invega Sustenna), quetiapine (Quetiapine Fumarate, Seroquel, Seroquel XR), risperidone (Risperidone, Risperdal, Risperdal Consta), ziprasidone (Ziprasidone Hydrochloride, Geodon)

Typical Antipsychotics (brand names in brackets): chlorpromazine (Chlorpromazine Hydrochloride, Chlorpromazine Hydrochloride Intensol, Promapar, Sonazine, Thorazine), fluphenazine (Fluphenazine, Fluphenazine Decanoate, Fluphenazine Hydrochloride, Permitil, Prolixin, Prolixin Decanoate, Prolixin Enanthate), haloperidol (Haloperidol, Haldol, Haldol Solutab, Haloperidol Decanoate, Haloperidol Intensol, Haloperidol Lactate), loxapine (Loxapine, Loxapine Succinate, Loxitane, Loxitane C, Loxitane IM), molindone (Moban), perphenazine (Perphenazine, Trilafon) pimozide (Orap), prochlorperazine (Prochlorperazine, Prochlorperazine Edisylate, Prochlorperazine Maleate, Compazine, Compro), thiothixene (Thiothixene, Thiothixene Hydrochloride, Thiothixene Hydrochloride Intensol, Navane), thioridazine (Thioridazine Hydrochloride, Thioridazine Hydrochloride Intensol, Mellaril, Mellaril-S), trifluoperazine (Trifluoperazine Hydrochloride, Stelazine)

Outcomes
Outcomes from primary research:

Medication adherence and persistence (role of dosage, time to discontinuation of treatment and associated impact on patient choices)
Patient insight into illness
Suicide-related behaviors, death by suicide
Functional capacity: any of the following – employment/personal earnings (income), social relatedness/functioning, encounters with legal system, sexual function/dysfunction
Health system utilization: time to hospitalization/re-hospitalization (due to mental illness and all-cause) and rates of hospitalization/re-hospitalization, rates emergency department visits, mean hospital bed days, LOS (hospitalization)
Patient satisfaction
Health-related QOL
Outcomes from existing systematic reviews:

Symptom response: in schizophrenia/schizophrenia-related psychoses (positive and negative symptoms, general psychopathology), in bipolar disorder (mood, motor activity/energy, sleep, speech, behavior)
Response rates with corresponding dose, duration of response, remission, relapse, speed of response, time to discontinuation of medication
Overdose safety
Adverse events (overall events, specific events, withdrawals due to adverse events, time to withdrawal due to adverse events). Adverse events to include:
Major: mortality, cerebrovascular disease-related events, development of diabetes mellitus, diabetic ketoacidosis, neuroleptic malignant syndrome, seizures, tardive dyskinesia, cardiomyopathies and cardiac arrhythmias, agranulocytosis
General: extrapyramidal effects, weight gain, agitation, constipation, sedation, elevated cholesterol, adverse events related to prolactin elevations, galactorrhea/bloody galactorrhea
Timing
Short-term outcomes will be defined as outcomes related to episodic medication use.

Long-term outcomes will be defined as outcomes occurring beyond 6-12 weeks.

Setting
No limitations have been set for clinical setting.

Definition of Terms
There is no consensus on how to define the medications to be included in this review (e.g., use of the terms first and second generation antipsychotics, typical and atypical antipsychotics). For the purposes of this review, the terms typical and atypical antipsychotics will be used.

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Comment Key Questions - AHRQ Effective Health Care Program